Melatonin and multiple sclerosis: antioxidant, anti-inflammatory and immunomodulator mechanism of action.

BACKGROUND: Melatonin is an indole hormone secreted primarily by the pineal gland that showing anti-oxidant, anti-inflammatory and anti-apoptotic capacity. It can play an important role in the pathophysiological mechanisms of various diseases. In this regard, different studies have shown that there is a relationship between Melatonin and Multiple Sclerosis (MS). MS is a chronic immune-mediated disease of the Central Nervous System. AIM: The objective of this review was to evaluate the mechanisms of action of melatonin on oxidative stress, inflammation and intestinal dysbiosis caused by MS, as well as its interaction with different hormones and factors that can influence the pathophysiology of the disease. RESULTS: Melatonin causes a significant increase in the levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione and can counteract and inhibit the effects of the NLRP3 inflammasome, which would also be beneficial during SARS-CoV-2 infection. In addition, melatonin increases antimicrobial peptides, especially Reg3ß, which could be useful in controlling the microbiota. CONCLUSION: Melatonin could exert a beneficial effect in people suffering from MS, running as a promising candidate for the treatment of this disease. However, more research in human is needed to help understand the possible interaction between melatonin and certain sex hormones, such as estrogens, to know the potential therapeutic efficacy in both men and women.

EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations.

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.

Structural and Functional Analysis of Female Sex Hormones against SARS-CoV-2 Cell Entry.

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.

Feminising hormone therapy reduces testicular ACE-2 receptor expression: Implications for treatment or prevention of COVID-19 infection in men.

It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.

COVID-19 in Africa: an ovarian victory?

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly attacks the respiratory system and is characterized by pneumonia, cytokine storm, coagulation disorders and severe immune downregulation. Although public health experts predicted worst outcomes in Africa, the incidence, hospitalization and mortality rates have been lower in Africa compared to other continents. Interestingly, lower incidence and mortality rates have been observed in women from Africa compared to their cohorts from other continents. Also, in the US non-Hispanic Black females have lower COVID-19 and death rates compared to their white counterparts. It's unclear why this significant difference exists; however, the ovarian function, genetics and immunological statuses could play a major role. Women of African descent have elevated levels of estrogen compared with Caucasians hence we anticipate that estrogen might offer some protection against the SARS-CoV-2 infections. The racial differences in lifestyle, age and inaccessibility to contraceptive usage might also play a role. Here, we provide insight on how the high levels of estrogen in African women might contribute to the lower cases and fatalities in Africa. Specifically, estrogen might offer protection against COVID-19 by suppressing hyper-production of cytokines, promoting anti-inflammatory cytokines, stimulating antibody production and suppressing endoplasmic reticulum (ER) stress. This will as well provide useful information on how future pandemics could be managed using Africa as a case study.

Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?

The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.